A1 adenosine receptor antagonists

ABSTRACT

wherein R 3  is Alk 14 ArR 16 , and wherein Alk 14  is C 1-8  straight or branched alkylene or alkenylene. 
           
         
       
    
     The present invention provides novel adenosine receptor antagonists, more particularly, A 1  adenosine receptor antagonists of formula (I). Pharmaceutical compositions comprising an A 1  adenosine receptor antagonist of formula (I) and a pharmaceutically acceptable carrier are further provided. Compositions also include diagnostic assay-type probes comprising a novel A 1  adenosine receptor antagonist of formula (I) that is labeled or conjugated with radioactive or non-radioactive material. Methods for treating A 1  adenosine receptor related disorders comprising administering an A 1  adenosine receptor antagonist of formula I are also disclosed. The novel A 1  adenosine receptor antagonist compositions of formula (I) find further use in diagnostic and imaging methods.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.10/861,677, filed Jun. 4, 2004, now U.S. Pat. No. 7,247,639 which claimsthe benefit of U.S. Provisional Patent Application Ser. No. 60/476,684filed Jun. 6, 2003, the disclosure of which is incorporated by referenceherein in its entirety.

FIELD OF THE INVENTION

The present invention concerns compounds useful as A₁ adenosine receptorantagonists, along with methods of use thereof.

BACKGROUND OF THE INVENTION

Adenosine receptors are involved in a vast number of peripheral andcentral regulatory mechanisms such as, for example, vasodilation,cardiac depression, inhibition of lipolysis, inhibition of insulinrelease and potentiation of glucagon release in the pancreas, andinhibition of neurotransmitter release from nerve endings.

In general, adenosine receptors can be divided into two main classes, A₁receptors which can inhibit, and A₂ receptors which can stimulateadenylate cyclase activity. One of the best known classes of adenosinereceptor antagonists are the xanthines which include caffeine andtheophylline. See e.g., Müller et al., J. Med. Chem. 33: 2822-2828(1990).

In general, many of these antagonists often exhibit poor watersolubility, and low potency or lack of selectivity for adenosinereceptors. Additionally, selective analogues of adenosine receptorantagonists have been developed through the “functionalized congener”approach. Analogues of adenosine receptor ligands bearing functionalizedchains have been synthesized and attached covalently to various organicmoieties such as amines and peptides. Attachment of the polar groups toxanthine congeners has been found to increase water solubility.Nonetheless, such developments have yet to fully address problemsassociated with potency and selectivity.

SUMMARY OF THE INVENTION

In one aspect, the invention is a compound of the general formula (I):

wherein;

-   -   R₁ is C₁₋₈ straight or branched alkyl optionally substituted        with one or more OR₅, NR₆R₇, or halogen groups,        -   wherein;            -   R₅ and R₆ are independently H, or C₁₋₈ straight or                branched alkyl;            -   R₇ is H, C₁₋₈ straight or branched alkyl, or Alk₁-OH,                -   wherein; Alk₁ is C₁₋₈ straight or branched alkylene;    -   R₂ is H, C₁₋₈ alkyl, Alk₂COOH, Alk₃COOR₈, Alk₄CONR₉R₁₀, Alk₅OH,        Alk₆SO₃H, Alk₇PO₃H₂, Alk₈OR₁₁, Alk₉OH or Alk₁₀NR₁₂R₁₃, or, when        R₃ is (CH₂)_(q)(C₆H₄)Q, R₂ is as defined above or is        Alk₁₁N(CH₃)Alk₁₂OH; and when R₃ is other than (CH₂)_(q)(C₆H₄)Q,        R₂ is as defined above or is Alk₁₃NR₁₄R₁₅;        -   wherein;            -   Alk₂ through Alk₁₃ are independently C₁₋₈ straight or                branched alkylene or alkenylene;            -   q is an integer ranging from 1 to 8;            -   Q is H, OH, NH₂, (CH₂)_(t) OH, or R_(13a)COOH, wherein t                is an integer ranging from 1 to 8;            -   R₈ through R₁₃, and R_(13a) are independently H, or C₁₋₈                straight or branched alkyl;            -   R₁₄ is H, CH₃, or (CH₂)_(p1)CH₃;            -   R₁₅ is H, CH₃, (CH₂)_(p2)CH₃ or (CH₂)_(m)OH,                -   wherein; p₁ and p₂ are independently integers from 1                    to 7, and m is an integer from 1 to 8;    -   R₃ is Alk₁₄ArR₁₆,        -   wherein;            -   Alk₁₄ is C₁₋₈ straight or branched alkylene or                alkenylene;            -   Ar is a 5- or 6-member aromatic ring containing 0 to 4                heteroatoms selected from N, O, and S, or is a bicyclic                9- or 11-member aromatic ring containing 0 to 6                heteroatoms selected from N, O, and S;            -   R₁₆ is H, OH, OR_(13b), NO₂, NH₂, CN, Alk₁₅OH, Alk₁₆NH₂,                NR₁₇R₁₈, NR₁₉COR_(19a), Alk₁₇COOR_(19b), SO₂R_(19c),                SO₃H, PO₃H₂ or halogen;                -   wherein;                -    Alk₁₅ through Alk₁₇ are independently C₁₋₈ straight                    or branched alkylene or alkenylene;                -    R_(13b) is H, or C₁₋₈ straight or branched alkyl;                -    R₁₇, through R₁₉ and R_(19a) through R_(19c) are                    independently H, an aromatic group, or C₁₋₈ straight                    or branched alkyl;    -   R₄ is

-   -   -   wherein;            -   r is an integer from 1 to 20;            -   R₂₀ is SO₃H, PO₃H₂, halogen, OR_(13c), COOR_(13d), NO₂,                NR₂₁R₂₂, NR₂₃COR_(23a), Alk₁₈COOR_(19d), SO₂R_(19e) or                Alk₁₈NR₂₄R₂₅ and when R₃ is other than (CH₂)_(q)(C₆H₄)Q,                R₂₀ is as defined above or is H, OH, NH₂ Alk₁₉OH,                Alk₂₀NH₂, or Alk₂₁COOH;                -   wherein;                -    Alk₁₉ through Alk₂₁ are independently C₁₋₈ straight                    or branched alkylene or alkenylene;                -    R_(13c) and R_(13d) are independently C₁₋₈ straight                    or branched alkyl;                -    R_(19d) and R_(19e) are independently H, an                    aromatic group or C₁₋₈ straight or branched alkyl;                -    R₂₁, through R₂₅ and R_(23a) are independently H,                    an aromatic group or C₁₋₈ straight or branched                    alkyl;                    wherein the compound optionally has one or more                    radioactive or non-radioactive label moieties                    wherein the label moieties are optionally connected                    to the compound through one or more spacer moiety;                    and salts, solvates and hydrates thereof.

A second aspect is a method of treating A₁ adenosine receptor relateddisorders in a mammal, including a human, comprising administering aneffective therapeutic amount of a compound of formula (I) or a salt,solvate or prodrug to the mammal in need there of.

A third aspect provides a pharmaceutical composition which comprises acompound of formula (I) and a pharmaceutically acceptable carrier.

A fourth aspect provides for diagnostic assay-type probes of a compoundof formula (I), wherein the probes are labeled or conjugated withradioactive or non-radioactive material.

A fifth aspect is the use of a compound of formula (I) as an imagingagent in diagnostic procedures such as MRI and PET.

A sixth aspect is the use of a compound of formula (I) in a cell orreceptor based assay.

A seventh aspect is the preparation of a compound of formula (I) for useas a medicament.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

The present invention will now be described more fully hereinafter, inwhich embodiments of the invention are shown. This invention may,however, be embodied in different forms and should not be construed aslimited to the embodiments set forth herein. Rather, these embodimentsare provided so that this disclosure will be thorough and complete, andwill fully convey the scope of the invention to those skilled in theart.

The terminology used in the description of the invention herein is forthe purpose of describing particular embodiments only and is notintended to be limiting of the invention. As used in the description ofthe invention and the appended claims, the singular forms “a”, “an” and“the” are intended to include the plural forms as well, unless thecontext clearly indicates otherwise.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs.

While the present invention is intended primarily for the treatment ofhuman subjects, it will be appreciated that other subjects, particularlymammalian subjects such as dogs, cats, horses, rabbits, etc., can alsobe treated by the methods of the present invention for veterinarypurposes.

“Halogen” as used herein refers to any suitable halo group, such asfluorine, chlorine, bromine, and iodine.

Compounds as described above may be prepared in accordance with thetechniques known in the art such as described in U.S. Pat. Nos.5,719,279, 5,786,360, 5,739,331, 6,489,332, the techniques described inthe Examples below, and variations of the foregoing that will beunderstandable to those skilled in the art of synthetic organicchemistry in light of the disclosure herein.

Specific examples of compounds of the present invention that can beprepared by such techniques include, but are not limited to, thefollowing:

-   3-[2-[4-(5-aminopentyl-3-amidocarboxypropanoyl)]aminophenyl]ethyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propylxanthine,-   3-[2-[4-(5-aminopentyl-3-amidocarboxypropanoyl)]aminophenyl]ethyl]-8-benzyl-7-(2,2-diethylamino]ethyl-1-propylxanthine,-   3-[2-[4-(5-aminopentyl-3-amidocarboxypropanoyl)]aminophenyl]ethyl]-8-benzyl-7-(2,2-diethylamino]ethyl-1-propylxanthine,    d-biotin amido adduct,-   3-[2-[4-(5-aminopentyl-3-amidocarboxypropanoyl)]aminophenyl]ethyl]-8-benzyl-7-(2,2-diethylamino]ethyl-1-propylxanthine,    Cy3B amido adduct,-   3-[2-[4-(5-aminopentanoyl)aminophenyl]ethyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propylxanthine,-   3-[2-[4-(5-aminopentanoyl)aminophenyl]ethyl]-8-benzyl-7-(2,2-diethylamino)ethyl-1-propylxanthine,-   3-[2-[4-(5-aminopentanoyl)aminophenyl]ethyl]-8-benzyl-7-(2,2-diethylamino)ethyl-1-propylxanthine,    d-biotin amido adduct,-   3-[2-[4-(5-aminopentanoyl)aminophenyl]ethyl]-8-benzyl-7-(2,2-diethylamino)ethyl-1-propylxanthine,    Cy3B amido adduct,-   3-[4-(4-aminophenyl)butyl]-8-benzyl-7-(2-ethylamino)ethyl-1-pentylxanthine,-   3-[4-(2-aminophenyl)butyl]-8-benzyl-7-(2-ethylamino)ethyl-1-propylxanthine,-   3-[4-(3-aminophenyl)butyl]-8-benzyl-7-(2-ethylamino)ethyl-1-propylxanthine,-   3-[4-(4-aminophenyl)butyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-pentylxanthine,-   3-[4-(2-aminophenyl)butyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propylxanthine,-   3-[4-(3-aminophenyl)butyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propylxanthine,-   3-[4-(3-aminophenyl)butyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-(3-fluoro)propylxanthine,-   3-[4-(3-aminophenyl)butyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-(3,3,3-trifluoro)propylxanthine,-   3-[4-(3-aminophenyl)butyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-(1,1,2,2,3,3,3-heptafluoro)propylxanthine,-   3-[2-(3-acetaminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propyl-8-[(pyrimidin-5-yl)methyl]xanthine,-   3-[2-(4-acetaminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-8-(3-methylsulfonobenzyl)-1-propylxanthine,-   8-(3-aminobenzyl)-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-pentyl-3-(2-phenylethyl)xanthine,-   8-(3-aminobenzyl)-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-(2-phenylethyl)-1-propylxanthine,-   8-(2-aminobenzyl)-3-[2-(2-aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propylxanthine,-   8-(2-aminobenzyl)-3-[2-(3-aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propylxanthine,-   8-(2-aminobenzyl)-3-[2-(3-aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-(3-fluoro)propylxanthine,-   3-[2-[2-(6-aminohexanoyl)aminophenyl]ethyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-(3-methoxypropyl)xanthine,-   3-[2-(4-aminophenyl)ethyl]-8-benzyl-1-butyl-7-[2-ethyl(2-hydroxyethyl)amino]ethylxanthine,-   3-[2-(2-aminophenyl)ethyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-pentylxanthine,-   3-[2-(4-aminophenyl)ethyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propylxanthine,-   3-[2-(4-aminophenyl)ethyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)-amino]ethyl-1-pentylxanthine,-   3-[2-(4-aminophenyl)ethyl]-8-benzyl-7-(2-ethylamino)ethyl-1-pentylxanthine,-   3-[2-(4-aminophenyl)ethyl]-8-benzyl-7-(2,2-diethylamino)ethyl-1-propylxanthine,-   3-[2-(4-aminophenyl)ethyl]-8-benzyl-7-[2-methyl(2-hydroxyethyl)amino]ethyl-1-propylxanthine,-   3-[2-(4-aminophenyl)ethyl]-8-benzyl-7-(2-methylamino)ethyl-1-propylxanthine,-   3-[2-(4-aminophenyl)ethyl]-8-benzyl-7-(2,2-dimethylamino)ethyl-1-propylxanthine,-   3-[2-(4-aminophenyl)ethyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-(3-fluoro)propylxanthine,-   3-[2-(4-aminophenyl)ethyl]-8-(3-chlorobenzyl)-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propylxanthine,-   3-[2-(2-aminophenyl)ethyl]-8-benzyl-1-(3-dimethylaminopropyl)-7-[2-ethyl(2-hydroxyethyl)amino]ethylxanthine,-   3-[2-(2-aminophenyl)ethyl]-8-benzyl-1-(3-dimethylaminopropyl)-7-(2,2-diethylamino)ethylxanthine,-   3-[2-(2-aminophenyl)ethyl]-8-benzyl-1-(3-dimethylaminopropyl)-7-(2-ethylamino)ethylxanthine,-   3-[2-(2-aminophenyl)ethyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-(3-methoxypropyl)xanthine,-   3-[2-(3-aminophenyl)ethyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-(3-methoxypropyl)xanthine,-   3-[2-(3-aminophenyl)ethyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-(3-methylsulfonopropyl)xanthine,-   3-[2-(3-aminophenyl)ethyl]-1-butyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-8-[(pyridazin-4-yl)methyl]xanthine,-   3-[2-(4-amino-3-chlorophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propyl-8-[(pyridazin-4-yl)methyl]xanthine,-   3-[2-(4-amino-2-chlorophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propyl-8-[(pyridazin-4-yl)methyl]xanthine,-   3-[2-(4-amino-2-fluorophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propyl-8-[(1H-pyrrol-3-yl)methyl]xanthine,-   3-[2-(3-aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propyl-8-[(1H-1,3,4-triazol-5-yl)methyl]xanthine,-   3-[2-(2-aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propyl-8-[(1H-1,2,4-triazol-5-yl)methyl]xanthine,-   3-[2-(3-aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-8-[(1,2,4-oxadiazol-5-yl)methyl]-1-propylxanthine,-   3-[2-(4-aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propyl-8-[(oxazol-2-yl)methyl]xanthine,-   3-[2-(2-aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-8-[(isoxazol-4-yl)methyl]-1-propylxanthine,-   3-[2-(2-aminophenyl)ethyl]-8-[(5-chloroisoxazol-4-yl)methyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propylxanthine,-   3-[2-(4-aminophenyl)ethyl]-8-(2,4-difluorobenzyl)-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propylxanthine,-   3-[2-(2-aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-8-[(5-fluoroisoxazol-4-yl)methyl]-1-pentylxanthine,-   3-[2-(4-aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-8-[(4-fluoro-2-oxazolyl)methyl]-1-propylxanthine,-   3-[2-(4-aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-8-[(is    othiazol-3-yl)methyl]-1-propyl-xanthine,-   3-[2-(3-aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propyl-8-[(pyrimidin-2-yl)methyl]xanthine,-   3-[2-(2-aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-8-[(4-fluoro-3-isothiazolyl)methyl]-1-propylxanthine,-   3-[2-(4-aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-8-[(5-fluoropyrimidin-2-yl)methyl]-1-propylxanthine,-   3-[2-(3-aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-8-[(1,3,4-oxadiazol-5-yl)methyl]-1-pentylxanthine,-   3-[2-(4-aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propyl-8-[(1H-pyrazol-3-yl)methyl]xanthine,-   3-[2-(3-aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propyl-8-[(1H-pyrazol-3-yl)methyl]xanthine,-   3-[2-(4-aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-pentyl-8-[(1H-pyrazol-3-yl)methyl]xanthine,-   3-[2-(2-aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propyl-8-[(pyrazin-2-yl)methyl]xanthine,-   3-[2-(2-aminophenyl)ethyl]-1-butyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-8-[(3-fluoropyrazin-2-yl)methyl]xanthine,-   3-[2-(2-aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-8-[(3-fluoropyrazin-2-yl)methyl]-1-pentylxanthine,-   3-[2-(2-aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-8-[(3-fluoropyrazin-2-yl)methyl]-1-propylxanthine,-   3-[2-(4-aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-pentyl-8-[(2-fluoro-1H-pyrazol-3-yl)methyl]xanthine,-   3-[2-(4-aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propyl-8-[(1H-pyrrol-3-yl)methyl]xanthine,-   3-[2-(2-aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propyl-8-[(1H-tetrazol-5-yl)methyl]xanthine,-   3-[2-(3-aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propyl-8-[(furan-3-yl)methyl]xanthine,-   3-[2-(4-aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propyl-8-[(furan-2-yl)methyl]xanthine,-   3-[2-(4-aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propyl-8-[(thiophen-3-yl)methyl]xanthine,-   3-[6-(4-aminophenyl)hexyl]-8-benzyl-7-(2-ethylamino)ethyl-1-pentylxanthine,-   3-[6-(2-aminophenyl)hexyl]-8-benzyl-7-(2-ethylamino)ethyl-1-propylxanthine,-   3-[6-(3-aminophenyl)hexyl]-8-benzyl-7-(2-ethylamino)ethyl-1-propylxanthine,-   3-[6-(3-aminophenyl)hexyl]-8-benzyl-7-(2-ethylamino)ethyl-1-(3-fluoro)propylxanthine,-   3-[6-(4-aminophenyl)hexyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-pentylxanthine,-   3-[6-(2-aminophenyl)hexyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propylxanthine,-   3-[6-(3-aminophenyl)hexyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propylxanthine,-   3-[6-(3-aminophenyl)hexyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-(3-fluoro)propylxanthine,-   8-benzyl-3-[2-(3-aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propylxanthine,-   8-benzyl-3-[2-(3-chlorophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propylxanthine,-   8-benzyl-3-[2-(2,4-difluorophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-pentylxanthine-   8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-[2-(3-nitrophenyl)ethyl]-1-propylxanthine,-   8-benzyl-7-(2-ethylamino)ethyl-3-[2-(3-nitrophenyl)ethyl]-1-propylxanthine,-   8-benzyl-7-(2,2-diethylamino)ethyl-3-[2-(3-nitrophenyl)ethyl]-1-propylxanthine,-   8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-[2-(isothiazol-3-yl)ethyl]-1-propylxanthine,-   8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-[2-(thiazol-3-yl)ethyl]-1-propylxanthine,-   8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-[2-(isoxazol-3-yl)ethyl]-1-propylxanthine,-   8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-[2-(1,3,4-oxadiazol-5-yl)ethyl]-1-pentylxanthine,-   8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-[2-(1,2,4-oxadiazol-5-yl)ethyl]-1-propylxanthine,-   8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-[2-(4-fluorophenyl)ethyl]-1-pentylxanthine,-   8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine,-   8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-[2-phenylethyl]-1-pentylxanthine,-   8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-[2-phenylethyl]-1-propylxanthine,-   3-[2-(4-bromophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propyl-8-[(4-pyridyl)methyl]xanthine,-   3-[2-(4-chlorophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propyl-8-[(4-pyridyl)methyl]xanthine,-   3-[2-(2,4-diaminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-8-[(5-fluoro-2-oxazolyl)methyl]-1-propylxanthine,-   7-(2,2-diethylamino)ethyl-3-(2-phenylethyl)-1-propyl-8-[(2-pyridyl)methyl]xanthine,-   7-(2,2-diethylamino)ethyl-3-[2-(3-fluorophenyl)ethyl]-8-[(1,3,4-oxadiazol-5-yl)methyl]-1-propylxanthine,-   7-(2,2-diethylamino)ethyl-3-[2-(3-nitrophenyl)ethyl]-1-propyl-8-[(pyridazin-4-yl)methyl]xanthine,-   7-(2,2-diethylamino)ethyl-3-(2-phenylethyl)-1-propyl-8-[(1H-pyrazol-3-yl)benzyl]xanthine,-   7-(2-ethylamino)ethyl-3-(2-phenylethyl)-1-propyl-8-[(2-pyridyl)methyl]xanthine,-   7-(2-ethylamino)ethyl-3-[2-(3-nitrophenyl)ethyl]-8-[(1,3,4-oxadiazol-5-yl)methyl]-1-propyllxanthine,-   7-(2-ethylamino)ethyl-3-[2-(2-nitrophenyl)ethyl]-8-[(4-fluoro-3-isothiazolyl)methyl]-1-propylxanthine,-   7-(2-ethylamino)ethyl-3-[2-(2-fluorophenyl)ethyl]-1-propyl-8-[(pyrazin-2-yl)methyl]xanthine,-   7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-[2-(2-fluorophenyl)ethyl]-1-propyl-8-[(pyrazin-2-yl)methyl]xanthine,-   7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-[2-(3-fluorophenyl)ethyl]-8-[(1,3,4-oxadiazol-5-yl)methyl]-1-propylxanthine,-   7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(1H-pyrazol-3-yl)methyl]xanthine,-   7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-[2-(3-nitrophenyl)ethyl]-8-[(1,3,4-oxadiazol-5-yl)methyl]-1-propyllxanthine,-   7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-[2-(2-nitrophenyl)ethyl]-1-propyl-8-[(1H-1,2,4-triazol-5-yl)methyl]xanthine,-   7-[2-ethyl(2-hydroxyethyl)amino]ethyl-8-[(4-fluoro-3-isothiazolyl)methyl]-3-[2-(2-nitrophenyl)ethyl]-1-propylxanthine,-   7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-[2-(3-nitrophenyl)ethyl]-1-propyl-8-[(pyridazin-4-yl)methyl]xanthine,-   7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-[2-(3-nitrophenyl)ethyl]-8-[(1,2,4-oxadiazol-5-yl)methyl]-1-propylxanthine,-   7-[2-ethyl(2-hydroxyethyl)amino]ethyl-8-[(1,2,4-oxadiazol-3-yl)benzyl]-3-(2-phenylethyl)-1-propylxanthine,-   7-[2-ethyl(2-hydroxyethyl)amino]ethyl-8-[(1,3,4-oxadiazol-5-yl)benzyl]-3-(2-phenylethyl)-1-propylxanthine,-   7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-(2-phenylethyl)-1-propyl-8-[(1H-pyrazol-3-yl)benzyl]xanthine,-   7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-pentyl-3-(2-phenylethyl)-8-[(3-pyridyl)methyl]xanthine,-   7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-(2-phenylethyl)-1-propyl-8-[(2-pyridyl)methyl]xanthine,    and-   7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-(2-phenylethyl)-1-propyl-8-[(4-pyridyl)methyl]xanthine-   3-[2-(4-aminophenyl)ethyl]-8-benzyl-7-(2-ethylamino)ethyl-1-propylxanthine    (example 5),-   3-[2-(4-aminophenyl)ethyl]-8-benzyl-7-(2,2-diethylamino)ethyl-1-propylxanthine    (example 6),-   3-[2-(4-aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-8-(4-fluorobenzyl)-1-propylxanthine    (example 7),-   3-[2-(4-aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propyl-8-[(3-pyridyl)methyl]xanthine    (example 8),-   3-[2-(4-aminophenyl)ethyl]-7-(2-ethylamino)ethyl-1-propyl-8-[(3-pyridyl)methyl]xanthine    (example 9),-   3-[2-(4-aminophenyl)ethyl]-7-(2,2-diethylamino)ethyl-1-propyl-8-[(3-pyridyl)methyl]xanthine    (example 10),-   3-[2-(4-aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propyl-8-[(thiophen-2-yl)methyl]xanthine    (example 11),-   3-[2-(4-aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propyl-8-[(4-thiazolyl)methyl]xanthine    (example 12),-   3-[2-(4-aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propyl-8-[(1H-tetrazol-5-yl)methyl]xanthine    (example 13),-   3-[2-(4-aminophenyl)ethyl]-7-(2-ethylamino)ethyl-1-propyl-8-[(1H-tetrazol-5-yl)methyl]xanthine    (example 14),-   3-[2-(4-aminophenyl)ethyl]-7-(2,2-diethylamino)ethyl-1-propyl-8-[(1H-tetrazol-5-yl)methyl]xanthine    (example 15),-   3-[2-(4-aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-8-(4-methylsulfonobenzyl)-1-propylxanthine    (example 16),-   3-[2-(4-aminophenyl)ethyl]-7-(2-ethylamino)ethyl-8-(4-methylsulfonobenzyl)-1-propylxanthine    (example 17),-   3-[2-(4-aminophenyl)ethyl]-7-(2,2-diethylamino)ethyl-8-(4-methylsulfonobenzyl)-1-propylxanthine    (example 18),-   3-[2-(4-aminophenyl)ethyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-(3-methoxypropyl)xanthine    (example 19),-   3-[2-(4-aminophenyl)ethyl]-8-benzyl-7-(2-ethylamino)ethyl-1-(3-methoxypropyl)xanthine    (example 20),-   3-[2-(4-aminophenyl)ethyl]-8-benzyl-7-(2,2-diethylamino)ethyl-1-(3-methoxypropyl)xanthine    (example 21),-   3-[2-(4-aminophenyl)ethyl]-8-benzyl-1-(3-dimethylaminopropyl)-7-[2-ethyl(2-hydroxyethyl)amino]ethylxanthine    (example 22),-   3-[2-(4-aminophenyl)ethyl]-8-benzyl-1-(3-dimethylaminopropyl)-7-(2-ethylamino)ethylxanthine    (example 23),-   3-[2-(4-aminophenyl)ethyl]-8-benzyl-7-(2,2-diethylamino)ethyl-1-(3-dimethylaminopropyl)xanthine    (example 24),-   3-[2-[4-(6-aminohexanoyl)aminophenyl]ethyl]-8-benzyl-7-(2,2-diethylamino)ethyl-1-propylxanthine    (example 25),-   3-[2-[4-(6-aminohexanoyl)aminophenyl]ethyl]-8-benzyl-7-(2,2-diethylamino)ethyl-1-propylxanthine,    Cy3B amido adduct (example 26),-   3-[2-[4-(6-aminohexyl-3-amidocarboxypropanoyl)]aminophenyl]ethyl]-8-benzyl-7-(2,2-diethylamino]ethyl-1-propylxanthine    (example 27),-   3-[2-[4-(6-aminohexyl-3-amidocarboxypropanoyl)]aminophenyl]ethyl]-8-benzyl-7-(2,2-diethylamino]ethyl-1-propylxanthine,    Cy3B amido adduct (example 28),-   3-[2-[4-(6-aminohexyl-3-amidocarboxypropanoyl)]aminophenyl]ethyl]-8-benzyl-7-(2,2-diethylamino]ethyl-1-propylxanthine,    d-biotin amido adduct (example 29),-   3-[2-(4-aminophenyl)ethyl]-8-benzyl-7-[1³H,2³H-[2-ethyl(2-hydroxyethyl)amino]ethyl]-1-propylxanthine    (example 30),-   3-[2-(4-aminophenyl)ethyl]-8-benzyl-7-[1³H,2³H-(2-ethylamino)ethyl]-1-propylxanthine    (example 31),-   3-[4-(4-aminophenyl)butyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propylxanthine    (example 32),-   3-[4-(4-aminophenyl)butyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propyl-8-(4-sulfonoxybenzyl)xanthine    (example 33),-   3-[4-(4-aminophenyl)butyl]-7-(2-ethylamino)ethyl-1-propyl-8-(4-sulfonoxybenzyl)xanthine    (example 34),-   3-[4-(4-aminophenyl)butyl]-7-(2,2-diethylamino)ethyl-1-propyl-8-(4-sulfonoxybenzyl)xanthine    (example 35),-   3-[4-(4-aminophenyl)butyl]-7-(2,2-dimethylamino)ethyl-1-propyl-8-(4-sulfonoxybenzyl)xanthine    (example 36),-   3-[2-(4-aminophenyl)ethyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-(3-methoxyethyl)xanthine,-   3-[2-(4-aminophenyl)ethyl]-8-benzyl-7-(2-ethylamino)ethyl-1-(3-methoxyethyl)xanthine,-   3-[2-(4-aminophenyl)ethyl]-8-benzyl-7-(2,2-diethylamino)ethyl-1-(3-methoxyethyl)xanthine,-   3-[2-(4-aminophenyl)ethyl]-8-benzyl-1-(3-dimethylaminoethyl)-7-[2-ethyl(2-hydroxyethyl)amino]ethylxanthine,-   3-[2-(4-aminophenyl)ethyl]-8-benzyl-1-(3-dimethylaminoethyl)-7-(2-ethylamino)ethylxanthine,-   3-[2-(4-aminophenyl)ethyl]-8-benzyl-7-(2,2-diethylamino)ethyl-1-(3-dimethylaminoethyl)xanthine,    or-   3-[4-(4-aminophenyl)butyl]-7-[2-methyl(2-hydroxyethyl)amino]ethyl-1-propyl-8-(4-sulfonoxybenzyl)xanthine.

The compounds of formula (I) may form salts with both organic andinorganic acid and bases. Likewise, the compounds of formula (I) mayform solvates including hydrates. All salts and solvates of thecompounds of formula (I) are within the scope of the present invention.While pharmaceutically acceptable salts and solvates are useful for thetreatment of mammals, including humans, non-pharmaceutically salts andsolvates may be useful as chemical intermediates, and thus, are withinthe scope of the present invention. Examples of suitable acids forpharmaceutically acceptable salt formation include, but are not limitedto, hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic,salicylic, ascorbic, maleic, methanesulfonic, benzenesulfonic,p-toluenesulfonic and the like. Any of the amine acid addition salts mayalso be used. The salts are prepared by contacting the free base form ofthe compound with an appropriate amount of the desired acid in a mannerknown to one skilled in the art.

Examples of suitable bases for pharmaceutically acceptable saltformation include, but are not limited to, ammonium hydroxide, sodiumhydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide,calcium hydroxide, ammonia, organic amines such as triethylamine, andthe like. The salts may be prepared by contacting the free acid form ofthe compound with an appropriate amount of the desired base in a mannerknown to one skilled in the art. An example of a suitable solvate is ahydrate. Solvates may be prepared by any appropriate method of the art.

The compounds of formula (I) may be administered per se or in the formof acid or basic salts, hydrates, solvates and pro-drugs thereof, inaccordance with known techniques, to carry out the methods describedherein.

Active compounds of the invention may be provided in the form ofprodrugs. The term “prodrug” refers to compounds that are transformed invivo to yield the parent compound of the above formulae, for example, byhydrolysis in blood. A thorough discussion is provided in T. Higuchi andV. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the A.C.S.Symposium Series and in Edward B. Roche, ed., Bioreversible Carriers inDrug Design, American Pharmaceutical Association and Pergamon Press,1987. See also U.S. Pat. No. 6,680,299. Examples include, but are notlimited to, a prodrug that is metabolized in vivo by a subject to anactive drug having at least some of the activity of the active compoundsas described herein, wherein the prodrug is an ester of an alcohol orcarboxylic acid group, if such a group is present in the compound; anacetal or ketal of an alcohol group, if such a group is present in thecompound; an N-Mannich base or an imine of an amine group, if such agroup is present in the compound; or a Schiff base, oxime, acetal, enolester, oxazolidine, or thiazolidine of a carbonyl group, if such a groupis present in the compound, such as described in U.S. Pat. Nos.6,680,324 and 6,680,322.

The compounds of the present invention can be useful in diagnosticassays. Accordingly, the invention also provides A₁ adenosine receptorantagonist compounds with radioactive or non-radioactive labels suitablefor executing such assays. Labeled compounds are useful as assay-typeprobes or conjugates, and to obtain quantitative binding measurements ofthe A₁ adenosine receptor antagonist compounds. As used herein, the term“assay-type probes” refers to those materials which are useful forenhancing the selectivity of the quantitative analysis of the A₁adenosine receptor compounds of the invention.

Examples of such assay-type probes and their diagnostic uses aredescribed in Jacobson, et al., U.S. Pat. No. 5,248,770 ('770). Theprobes are—useful because they have little adverse effect on theaffinity of the compounds of the present invention. Nuclear markers(also referred to a “labels”) include, but are not limited to, nuclearspin markers, e.g. a ¹⁹F MRI probe, radioactive markers, e.g., ¹⁸F, ¹¹C,¹⁵N, ¹²⁵I, and ³H (tritium) isotope marker, and complexes of metal atomsor metal ions and chelating agents. Typically the metal or metal ion inthe complex will have a heavy, radioactive nucleus. The marker atoms maybe chemically bonded to, or complexed, e.g. chelated, with, a compoundof formula (I) or may be one of the integral carbon or heteroatom of acompound of formula (I).

Such labeled compounds can be used for in vitro or in vivo imaging ofadenosine receptors, especially in tissues, including but not limited tothe brain, heart, liver, kidney, and lungs to obtain quantitativemeasurements of adenosine receptors and determine the distribution andregional binding characteristics of adenosine receptors in tissue. Theseassay-type probes may be used, inter alia, in connection with suchdiagnostic techniques as magnetic resonance imaging (MRI) and positronemission tomography (PET). See, for example, Myer, et al.,Quantification of cerebral A₁ Adenosine Receptors in Humans Using[18F]CPFPX and PET. J Cerebral Blood Flow & Metabolism 24:323-333, 2004and Wakabayashi, et al., A PET Study of Adenosine AI Receptor in theAnesthetized Monkey Brain, Nuclear Med &Biol 27:401-406, 2000. Anexemplary metal ion is a radioactive isotope of technetium or indium. Anexemplary chelating agent is diethylenetriamine pentaacetic acid.

Various non-radioactive materials can be used in labeling the present A₁adenosine receptor compounds. Numerous examples are presented in U.S.Pat. No. 5,248,770. Biotin is a well known non-radioactive label forsuch probes, as described in R. W. Old et al. Principals of GeneManipulation, 4th ed: 328-331 (1989). To facilitate labeling thecompounds with biotin or any other appropriate label, a spacer componentor moiety may be added to a compound of the present invention by anysuitable method taught in the art, e.g. see U.S. Pat. No. 5,248,770.Exemplary spacer moieties include, but are not limited to, anoligopeptide, triglycidyl, N-hydroxysuccinimide ester,succinimidyl-thiohexane (6-thiohexyl-3-amidocarboxypropanoyl),succinimidyl hexamethyleneamine (6-aminohexyl-3-amidocarboxypropanoyl),succinimidyl-cadaverine (5-aminopentyl-3-amidocarboxypropanoyl), andsuccinimidyl-hexylmaleimide(6-N-maleimidohexyl-3-amidocarboxypropanoyl).

A non-radioactive label, e.g. biotin, may be bonded to any suitablelinkage provided by substituents on the compound structure in accordancewith any suitable technique taught in the art. For example, referring tothe compounds of formula (I) as defined herein, biotin may be bonded toone or more of the hydroxy groups, amino groups or carboxyl groupspresent such as at the R₁ through R₄ positions on the compound.Additionally, the biotin may be bonded to one or more of the hydroxylgroups that may be present at the R₁ through R₄ positions on thecompound. The biotin-labeled probes may be detected through appropriateand known analytical techniques

Fluorescent compounds, typically fluorescent dyes, may also be employedas a non-radioactive labels and are applied to appropriate locations onthe compounds of the invention as described above. Such dyes include,but are not limited to, tetramethylrhodamine, fluoresceinisothiocyanate, Cy3, (see Waggoner, et al., U.S. Pat. No. 5,268,486,Dec. 7, 1993) or Cy3B (see Waggoner et al., U.S. Pat. No. 6,133,445,Oct. 17, 2000) and mixtures thereof. Other non-radioactive materialsinclude for example, nitrobenzoxadiazole;2,2,6,6-tetramethyl-piperindinyloxy-4-isothiocyanate; luminescent dyes;obelin; and mixtures thereof, which may be applied in an analogousmanner as fluorescent compounds.

The skilled artisan will appreciate that also within the scope of theinvention is the use of the compounds of formula (I) marked with aradioactive or non-radioactive label in in vitro assays. For example,such marked compounds may be used in clinical cell based assays and inreceptor based assays. Such assays include, but are not limited to,radioligand binding assays, high throughput screening assays, and flowcytometry based assays, for example fluorescence-activated cell sorting(FACS) based assays. Examples of such assays include, but are notlimited to, radioimmunoassay and enzyme-linked immunosorbent assays(ELISA) (see, e.g. Nelson, et al., Lehninger Principles of Biochemistry,231, Worth, N.Y., (2000).

The invention is also directed to pharmaceutical compositions whichinclude compounds of the present invention and a pharmaceuticallyacceptable carrier. The pharmaceutical compositions described herein canbe prepared by any applicable method of the art. The pharmaceuticalcomposition is particularly useful in applications relating to organpreservation in vivo or in situ, perfusion of an isolated organ eitherremoved or contained within the body (e.g., when an organ is transportedfor transplantation), cardiopulmonary bypass, perfusion of an extremityor limb, and the like. The compounds may be used in intra-articular,intra-thecal, gastrointestinal, and genital urinary applications, aswell as in any cavity or lumen such as, for example, the thoracic cavityor ear canal.

While the present invention is intended primarily for the treatment ofhuman subjects, it will be appreciated that other subjects, particularlymammalian subjects such as dogs, cats, horses, rabbits, etc., can alsobe treated by the methods of the present invention for veterinarypurposes

The pharmaceutical compositions may be employed, as an example, in oraldosage form as a liquid composition. Such liquid compositions caninclude suspension compositions or syrup compositions and can beprepared with such carriers as water; a saccharide such as sucrose,sorbitol, fructose, and the like; a glycol such as polyethyleneglycol,polypropyleneglycol, and the like; an oil such as sesame oil, olive oil,soybean oil, and the like; an antiseptic such as p-hydroxy-benzoic acidesters and the like; and a flavor component such as a fruit flavor or amint flavor.

The pharmaceutical compositions may also be in the form of powder,tablets, capsules, and tablets and can be prepared with variouscarriers. Suitable carriers include, but are not limited to, lactose,glucose, sucrose, mannitol, and the like; disintegrators such as starch,sodium alginate, and the like; binders such as polyvinyl alcohol,hydroxypropyl cellulose, gelatin, and the like; surfactants such as, forexample, fatty acid esters; and plasticizers such as, for example,glycerins. The composition of the present invention is especially usefulwhen applied sublingually. It should be noted that in the preparation ofthe tablets and capsules, a solid pharmaceutical carrier is used.Advantageously, the pharmaceutical compositions may be used in the formof, for example, eye drops or an aerosol.

Other types of pharmaceutical compositions may be employed in the formof a suppository, a nasal spray, and an injectable solution. Thesecompositions are prepared using appropriate aqueous solutions which mayinclude, but are not limited to, distilled water, and saline and bufferadditives. Other components may be employed such as organic materialsincluding neutral fatty bases. Additionally, the pharmaceuticalcompositions may be utilized in a transdermal application.

Biopolymers may be used as carriers in the above pharmaceuticalcompositions. Exemplary biopolymers may include, for example, proteins,sugars, lipids, or glycolipids. See, e.g., PCT Application WO 02/095391(Published Nov. 22, 2002).

The A₁ receptor antagonists of the present invention are particularlyuseful as, for example, anti-allergenics, anti-inflammatory agents, CNSstimulants, diuretics, anti-asthmatics, cardiotonics, coronaryvasodilators, and anti-tussives and as agents for the treatment of viralor retroviral infections and immune deficiency disorders such asacquired immunodeficiency syndrome (AIDS).

The present invention also provides methods of treating A₁ adenosinereceptor related disorders, such disorders including, but not limitedto, congestive heart failure, hypertension, such as systemichypertension and pulmonary hypertension, ischemia-reperfusion organinjury, endotoxin-related tissue injury, renal failure, Alzheimer'sdisease, depression, obesity, asthma, diabetes, cystic fibrosis,allergic conditions, including, but not limited to allergic rhinitis andanaphylactic shock, autoimmune disorders, inflammatory disorders,chronic obstructive pulmonary disorders, chronic cough, coronary arterydisease, biliary colic, postoperative ileus, fibrosis, sclerosis, AdultRespiratory Distress Syndrome (ARDS), Acute Lung Injury (ALI), SevereAcute Respiratory Syndrome (SARS), septicemia, substance abuse, drugdependence, Parkinson's disease, and acquired immunodeficiency syndrome(AIDS).

The dosage of the active agent will depend upon the condition beingtreated, the age and condition of the subject, the route ofadministration, etc. In general, the dosage can be determined inaccordance with known techniques. In one embodiment, the dosage of theactive agent may, for example, be from 1 or 10 to 300 or 800 mg peradult subject.

The compounds described herein may be used alone or in combination withother compounds for the treatment of the disorders described herein,including, but not limited to, those compounds described in PCTApplication, WO 03/103675, published Dec. 18, 2003.

Thus, according to other embodiments of the invention, the presentinvention relates to a method of treating A₁ adenosine receptor-relateddisorders, comprising concurrently administering:

(a) an A₁ adenosine receptor antagonist as described above, or apharmaceutically acceptable salt thereof, with

(b) an additional active agent such as a compound selected from thegroup consisting of fluticasone propionate, salmeterol, theophylline, A₁adenosine receptor antagonists, A_(2a) adenosine receptor agonists,A_(2b) adenosine receptor antagonists, A₃ adenosine receptorantagonists, P_(2y) purinoceptor agonists, and P_(2x) purinoceptorantagonists, and combinations thereof, in an effective amount to treatthe A₁ adenosine receptor-related disorder.

As used herein, “effective amount” or “effective therapeutic amount”refers to a nontoxic but sufficient amount of the compound to providethe desired pharmacological effect, including but not limited to,improvement in the condition of the subject (e.g., in one or moresymptoms), delay in the progression of the condition, prevention ordelay of the onset of the disease or illness, etc.

As pointed herein, the exact amount required will vary from subject tosubject, depending on age, general condition of the subject, theseverity of the condition being treated, the particular biologicallyactive agent administered, and the like. An appropriate “effective”amount in any individual case may be determined by one of ordinary skillin the art by reference to the pertinent texts and literature and/or byusing routine experimentation.

An effective amount of a prodrug of the present invention is the amountof prodrug that must be metabolized with in the body or a mammal, suchas a human, to yield and an effective amount of a compound of formula(I).

The present invention relates to methods of treating A₁ adenosinereceptor-related disorders, comprising concurrently administering an A₁adenosine receptor antagonist as described above with at least oneadditional active agent such as described above effective to treat A₁adenosine receptor-related disorders, wherein the A₁ adenosinereceptor-related disorder is as described above.

Administration of compounds in combination may be carried out in likemanner as described above, with the active compound and the additionalactive agent being administered in the same or different carrier.Pharmaceutical formulations containing such combinations of activeagents may also be prepared in like manner as described above.

The present invention is explained in greater detail in the followingnon-limiting Examples.

EXAMPLE 1 Synthesis of5,6-Diamino-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (6)

Step a: Conversion of 4-Nitrophenethylamine Hydrochloride (1) to1-[2-(4-Nitrophenyl)ethyl]-1′-propylurea (2)

To a slurry of 777 gm of 4-nitrophenethylamine hydrochloride (1) and11.2 L of toluene was added slowly, 620 mL of triethylamine and thismixture was stirred for 30 min. at room temperature. To this suspensionwas then added slowly, 398 mL of n-propyl isocyanate, and the mixturewas stirred overnight at room temperature to give a solid precipitate.The heterogeneous mixture was filtered and the isolated solids werewashed with 1.5 L of toluene and then air dried. The 2.3 kg of crudeproduct was stirred with 6 L of water to dissolve residual triethylaminehydrochloride. The solids were isolated by filtration and air dried.This material was dissolved in 4 L of absolute ethanol and 1 L of waterwas added to induce crystallization. The solids were filtered, washedwith 2 L of 1:1 ethanol-water and air dried to yield a first crop of 880gm of 1-[2-(4-nitrophenyl)ethyl]-1′-propylurea (2). Therecrystallization mother liquors yielded an additional 39.8 gm of1-[2-(4-nitrophenyl)ethyl]-1′-propylurea (2).

Step b: Conversion of 1-[2-(4-Nitrophenyl)ethyl]-1′-propylurea (2) to1′-Cyanoacetyl-1-[2-(4-nitrophenyl)ethyl]-1′-propylurea (3)

A thick mixture of 920 gm of 1-[2-(4-nitrophenyl)ethyl]-1′-propylurea(2) and 1.0 L of acetic anhydride was stirred and warmed to ca. 50degrees C. To this mixture was added 343.2 gm of cyanoacetic acid and0.5 L of acetic anhydride and this homogeneous mixture was stirred at80-85 degrees C. for three hours. The mixture was cooled andconcentrated under vacuum to remove acetic acid and residual aceticanhydride. The residue was triturated successively with 1.0 L portionsof water, acetonitrile, toluene and ethyl acetate. The residue was thendried under vacuum to yield 1261 gm of a 2:1 mixture of1′-cyanoacetyl-1-[2-(4-nitrophenyl)ethyl]-1′-propylurea (3) and itsundesired isomer 1-cyanoacetyl-1-[2-(4-nitrophenyl)ethyl]-1′-propylurea.This material was dissolved in 2.2 L of hot ethyl acetate to which ca.750 mL of hexanes were added to the cloud point and the mixture wasallowed to cool to room temperature to induce crystallization.Filtration of the solid and air drying yielded 363 gm of1′-cyanoacetyl-1-[2-(4-nitrophenyl)ethyl]-1′-propylurea (3). If needed,additional recrystallizations from ethyl acetate-hexanes could becarried out to provide pure1′-cyanoacetyl-1-[2-(4-nitrophenyl)ethyl]-1′-propylurea (3).

Step c: Conversion of1′-Cyanoacetyl-1-[2-(4-nitrophenyl)ethyl]-1′-propylurea (3) to6-Amino-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (4)

A mixture of ca. 2N sodium hydroxide was produced by dissolving 336 gmof solid sodium hydroxide in 4.2 L of water. To this warm solution wasadded, in portions, 312 gm of1′-cyanoacetyl-1-[2-(4-nitrophenyl)ethyl]-1′-propylurea (3) and themixture was stirred for 1 hour at 80 degrees C., then was cooled to roomtemperature with stirring to induce crystallization. The solids wereisolated by filtration, washed with four 500 mL portions of water andvacuum dried at 65 degrees C. to yield 232 gm of crude6-amino-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (4).

Step d: Conversion of 6-Amino-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil(4) to 6-Amino-5-nitroso-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (5)

To a solution of 232 gm of crude6-amino-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (4), 4.0 L of waterand ca. 2.0 L of ethanol at 80 degrees C. was added 55.3 gm of sodiumnitrite in one portion, followed by the dropwise addition of 100 mL ofglacial acetic acid. After stirring at 80 degrees C. for 20 minutes themixture was allowed to cool to near room temperature, then was chilledin an ice bath to effect crystallization. The solids were isolated byfiltration, washed with two 1.0 L portions of water and dried undervacuum to yield 244 gm of purple colored6-amino-5-nitroso-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (5).

Step e: Conversion of6-Amino-5-nitroso-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (5) to5,6-Diamino-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (6)

A mixture of 243 gm of6-amino-5-nitroso-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (5), and 2.1L of water was heated to reflux and 528 mL of a 50% aqueous solution ofammonium sulfide was added with stirring to control foaming. The darksolution was stirred at 90-100 degrees C. for 30 min. and allowed tocool with stirring for 1.5 hours. The mixture was then chilled in an icebath to fully effect crystallization. The solids were isolated byfiltration, washed with three 500 mL portions of water and dried undervacuum to yield 219 gm of a dark solid. This material was recrystallizedfrom 1.0 L of acetonitrile to yield two crops totaling 169.5 gm of5,6-diamino-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (6).

EXAMPLE 2 Synthesis of8-Benzyl-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine (9)

A solution of 44.9 gm of phenylacetic acid in 630 mL ofdimethylformamide (DMF) was chilled in an ice water bath and 63.38 gm of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) wasadded followed by 5.24 gm of 4-dimethylaminopyridine (DMAP). Thismixture was stirred at ca. 4 degrees C. for 30 minutes and 100 gm of5,6-diamino-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (6) was added inone portion. This mixture was stirred for 60 hr at room temperature. Thedark homogeneous solution was poured into 700 mL of ice water withstirring to effect precipitation. The solids were isolated byfiltration, washed with three 100 mL portions of water and dried undervacuum to yield 103 gm of a mixture of5-amino-1-[2-(4-nitrophenyl)ethyl]-6-phenacetoamino-3-propyluracil (7)and 6-amino-1-[2-(4-nitrophenyl)ethyl]-5-phenacetoamino-3-propyluracil(8) intermediates. These solids were dissolved in 450 mL of p-dioxane,600 mL of 2N aqueous sodium hydroxide was added and the mixture washeated at reflux for one hr. The solution was then chilled in an icewater bath and the pH adjusted to pH 4 with ca. 100 mL of concentratedhydrochloric acid to yield a precipitate. The solids were isolated byfiltration, washed with three 100 mL portions of water and dried undervacuum to yield 82 gm of an orange solid. Recrystallization from hotethyl acetate afforded 58.0 gm of8-benzyl-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine (9).

EXAMPLE 3 Synthesis of8-Benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine

A mixture of 2.1 gm of8-benzyl-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine (9), 1.02 gm ofsodium carbonate, 3.82 ml of 1,2-dichloroethane and 0.59 ml of2-(ethylamino)ethanol was heated in a steel pressure vessel under argonat 120 degrees C. for 3-5 hours*. The mixture was then cooled and ventedto the atmosphere. The semisolid reaction mixture was triturated severaltimes with 5-10 ml portions of methanol followed by methylene chlorideand the combined solutions were evaporated to dryness. The residue waspurified by column chromatography on silica gel using a gradient of 1:1ethyl acetate-hexanes, ethyl acetate and 5% methanol in ethyl acetate.The appropriate fractions were collected and evaporated to dryness toyield a light orange solid of8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine.

EXAMPLE 4 Synthesis of3-[2-(4-Aminophenyl)ethyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)-amino]ethyl-1-propylxanthineFree Base and3-[2-(4-Aminophenyl)ethyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)-amino]ethyl-1-propylxanthineDihydrochloride Salt

To a mixture of 9.4 gm of8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthinein 400 ml of tetrahydrofuran under inert gas was added 1.2 gm of 10%palladium on carbon catalyst followed by the dropwise addition of 12 mlof hydrazine hydrate. The mixture was stirred for 2 hours at which timegas evolution subsided. An additional 600 mg of 10% palladium on carboncatalyst was added, followed by 5 ml of additional hydrazine hydrate.Additional catalyst and hydrazine hydrate were added as needed tocomplete the reaction. The reaction mixture was then filtered throughCelite and evaporated to dryness to yield an orange oil. Purification bysilica gel column chromatography afforded purified solid3-[2-(4-aminophenyl)ethyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)-amino]ethyl-1-propylxanthinefree base which was dissolved in 75 ml of tetrahydrofuran. To thissolution was added 15 ml of 4N hydrogen chloride in p-dioxane, whichgave a white precipitate. This precipitate was stirred as a slurry,collected by filtration and vacuum dried to afford3-[2-(4-aminophenyl)ethyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)-amino]ethyl-1-propylxanthinedihydrochloride salt, m.p. 230-231 degrees C. (uncorrected).

EXAMPLE 5 Synthesis of3-[2-(4-Aminophenyl)ethyl]-8-benzyl-7-(2-ethylamino)ethyl-1-propylxanthineFree Base or Hydrochloride Salts

By the method of Example3,8-benzyl-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine, is reacted withsodium carbonate, 1,2-dichloroethane and ethylamine to yield8-benzyl-7-(2-ethylamino)ethyl-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine.By the method of Example 4,8-benzyl-7-(2-ethylamino)ethyl-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthineis reduced with hydrazine hydrate or hydrogen gas in the presence of apalladium catalyst to yield3-[2-(4-aminophenyl)ethyl]-8-benzyl-7-(2-ethylamino)ethyl-1-propylxanthinefree base. The corresponding dihydrochloride salt is then made onexposure to an excess of hydrogen chloride in solution.

EXAMPLE 6 Synthesis of3-[2-(4-Aminophenyl)ethyl]-8-benzyl-7-(2,2-diethylamino)ethyl-1-propylxanthineFree Base or Hydrochloride Salts

By the method of Example3,8-benzyl-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine (9), is reactedwith sodium carbonate, 1,2-dichloroethane and diethylamine to yield8-benzyl-7-(2,2-diethylamino)ethyl-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine.By the method of Example4,8-benzyl-7-(2,2-diethylamino)ethyl-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthineis reduced with hydrazine hydrate or hydrogen gas in the presence of apalladium catalyst to yield3-[2-(4-aminophenyl)ethyl]-8-benzyl-7-(2,2-diethylamino)ethyl-1-propylxanthinefree base. The corresponding dihydrochloride salt is then made onexposure to an excess of hydrogen chloride in solution.

EXAMPLE 7 Synthesis of3-[2-(4-Aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-8-(4-fluorobenzyl)-1-propylxanthineFree Base or Hydrochloride Salts

By the method of Example 2,4-fluorophenylacetic acid is reacted with5,6-diamino-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (6) to yield8-(4-fluorobenzyl)-3-[2-(4-nitrophenyl)ethyl]1-propylxanthine. By themethods of Example 3 and Example4,8-(4-fluorobenzyl)-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine isalkylated with a mixture of 1,2-dichloroethane and2-(ethylamino)ethanol, to afford7-[2-ethyl(2-hydroxyethyl)amino]ethyl-8-(4-fluorobenzyl-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine,which, in turn, is reduced with hydrazine hydrate or hydrogen gas in thepresence of a palladium catalyst to yield3-[2-(4-aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-8-(4-fluorobenzyl)-1-propylxanthinefree base. The corresponding dihydrochloride salt is then made onexposure to an excess of hydrogen chloride in solution.

EXAMPLE 8 Synthesis of3-[2-(4-Aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propyl-8-[(3-pyridyl)methyl]xanthineFree Base or Hydrochloride Salts

By the method of Example 2,3-pyridylacetic acid is reacted with5,6-diamino-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (6) to yield3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(3-pyridyl)methyl]xanthine. Bythe method of Example 3, this substance is alkylated with a mixture of1,2-dichloroethane and 2-(ethylamino)ethanol to yield7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(3-pyridyl)methyl]xanthine.By the method of Example 4 this substance is reduced with hydrazinehydrate or hydrogen gas in the presence of a palladium catalyst to yield3-[2-(4-aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propyl-8-[(3-pyridyl)methyl]xanthinefree base. The corresponding hydrochloride salt is then made on exposureto an excess of hydrogen chloride in solution.

EXAMPLE 9 Synthesis of3-[2-(4-Aminophenyl)ethyl]-7-(2-ethylamino)ethyl-1-propyl-8-[(3-pyridyl)methyl]xanthineFree Base or Hydrochloride Salts

By the method of Example 2,3-pyridylacetic acid is reacted with5,6-diamino-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (6) to yield3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(3-pyridyl)methyl]xanthine. Bythe method of Example 3, this substance is reacted with sodiumcarbonate, 1,2-dichloroethane and ethylamine to yield4,7-(2-ethylamino)ethyl-3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(3-pyridyl)methyl]xanthine.By the method of Example 4,7-(2-ethylamino)ethyl-3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(3-pyridyl)methyl]xanthineis reduced with hydrazine hydrate or hydrogen gas in the presence of apalladium catalyst to yield3-[2-(4-aminophenyl)ethyl]-7-(2-ethylamino)ethyl-1-propyl-8-[(3-pyridyl)methyl]xanthinefree base. The corresponding hydrochloride salt is then made on exposureto an excess of hydrogen chloride in solution.

EXAMPLE 10 Synthesis of3-[2-(4-Aminophenyl)ethyl]-7-(2,2-diethylamino)ethyl-1-propyl-8-[(3-pyridyl)methyl]xanthineFree Base or Hydrochloride Salts

By the method of Example 3,3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(3-pyridyl)methyl]xanthine, isreacted with sodium carbonate, 1,2-dichloroethane and diethylamine toyield7-(2,2-diethylamino)ethyl-3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(3-pyridyl)methyl]xanthine.By the method of Example4,7-(2,2-diethylamino)ethyl-3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(3-pyridyl)methyl]xanthineis reduced with hydrazine hydrate or hydrogen gas in the presence of apalladium catalyst to yield3-[2-(4-aminophenyl)ethyl]-7-(2,2-diethylamino)ethyl-8-1-propyl-8-[(3-pyridyl)methyl]xanthinefree base. The corresponding hydrochloride salt is then made on exposureto an excess of hydrogen chloride in solution.

EXAMPLE 11 Synthesis of3-[2-(4-Aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propyl-8-[(thiophen-2-yl)methyl]xanthineFree Base or Hydrochloride Salts

By the method of Example 2,2-thiopheneacetic acid is reacted with5,6-diamino-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (6) to yield3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(thiophen-2-yl)methyl]xanthine.By the method of Example 3, this substance is alkylated with a mixtureof 1,2-dichloroethane, sodium carbonate and 2-(ethylamino)ethanol toyield7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(thiophen-2-yl)methyl]xanthine.By the method of Example 4 this substance is reduced with hydrazinehydrate or hydrogen gas in the presence of a palladium catalyst to yield3-[2-(4-aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propyl-8-[(thiophen-2-yl)methyl]xanthinefree base. The corresponding dihydrochloride salt is then made onexposure to an excess of hydrogen chloride in solution.

EXAMPLE 12 Synthesis of3-[2-(4-Aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propyl-8-[(4-thiazolyl)methyl]xanthineFree Base or Hydrochloride Salts

By the method of Example 2,4-thiazolylacetic acid is reacted with5,6-diamino-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (6) to yield3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(4-thiazolyl)methyl]xanthine. Bythe method of Example 3, this substance is alkylated with a mixture of1,2-dichloroethane, sodium carbonate and 2-(ethylamino)ethanol to yield7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(4-thiazolyl)methyl]xanthine.By the method of Example 4 this substance is reduced with hydrazinehydrate or hydrogen gas in the presence of a palladium catalyst to yield3-[2-(4-aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propyl-8-[(4-thiazolyl)methyl]xanthinefree base. The corresponding hydrochloride salt is then made on exposureto an excess of hydrogen chloride in solution.

EXAMPLE 13 Synthesis of3-[2-(4-Aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propyl-8-[(1H-tetrazol-5-yl)methyl]xanthineFree Base or Hydrochloride Salts

By the method of Example 2,1H-tetrazole-5-acetic acid is reacted with5,6-diamino-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (6) to yield3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(1H-tetrazol-5-yl)methyl]xanthine.By the method of Example 3, this substance is alkylated with a mixtureof 1,2-dichloroethane, sodium carbonate and 2-(ethylamino)ethanol toyield7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(1H-tetrazol-5-yl)methyl]xanthine.By the method of Example 4 this substance is reduced with hydrazinehydrate or hydrogen gas in the presence of a palladium catalyst to yield3-[2-(4-aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propyl-8-[(1H-tetrazol-5-yl)methyl]xanthinefree base. The corresponding hydrochloride salt is then made on exposureto an excess of hydrogen chloride in solution.

EXAMPLE 14 Synthesis of3-[2-(4-Aminophenyl)ethyl]-7-(2-ethylamino)ethyl-1-propyl-8-[(1H-tetrazol-5-yl)methyl]xanthineFree Base or Hydrochloride Salts

By the method of Example 2,1H-tetrazole-5-acetic acid is reacted with5,6-diamino-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (6) to yield3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(1H-tetrazol-5-yl)methyl]xanthine.By the method of Example 3, this substance is alkylated with a mixtureof 1,2-dichloroethane, sodium carbonate, and ethylamine to yield7-(2-ethylamino)ethyl-3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(1H-tetrazol-5-yl)methyl]xanthine.By the method of Example4,7-(2-ethylamino)ethyl-3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(1H-tetrazol-5-yl)methyl]xanthineis reduced with hydrazine hydrate or hydrogen gas in the presence of apalladium catalyst to yield3-[2-(4-aminophenyl)ethyl]-7-(2-ethylamino)ethyl-1-propyl-8-[(1H-tetrazol-5-yl)methyl]xanthinefree base. The corresponding hydrochloride salt is then made on exposureto an excess of hydrogen chloride in solution.

EXAMPLE 15 Synthesis of3-[2-(4-Aminophenyl)ethyl]-7-(2,2-diethylamino)ethyl-1-propyl-8-[(1H-tetrazol-5-yl)methyl]xanthineFree Base or Hydrochloride Salts

By the method of Example 3,3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(1H-tetrazol-5-yl)methyl]xanthine,is reacted with sodium carbonate, 1,2-dichloroethane and diethylamine toyield7-(2,2-diethylamino)ethyl-3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(1H-tetrazol-5-yl)methyl]xanthine.By the method of Example4,7-(2,2-diethylamino)ethyl-3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(1H-tetrazol-5-yl)methyl]xanthineis reduced with hydrazine hydrate or hydrogen gas in the presence of apalladium catalyst to yield3-[2-(4-aminophenyl)ethyl]-7-(2,2-diethylamino)ethyl-8-1-propyl-8-[(1H-tetrazol-5-yl)methyl]xanthinefree base. The corresponding hydrochloride salt is then made on exposureto an excess of hydrogen chloride in solution.

EXAMPLE 16 Synthesis of3-[2-(4-Aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-8-(4-methylsulfonobenzyl)-1-propylxanthineFree Base or Hydrochloride Salts

By the method of Example 2,4-methylsulfonophenylacetic acid is reactedwith 5,6-diamino-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (6) to yield3-[2-(4-nitrophenyl)ethyl]-8-(4-methylsulfonobenzyl)-1-propylxanthine.By the method of Example 3,3-[2-(4-nitrophenyl)ethyl]-8-(4-methylsulfonobenzyl)-1-propylxanthine,is reacted with sodium carbonate, 1,2-dichloroethane and2-(ethylamino)ethanol to yield7-[2-ethyl(2-hydroxyethyl)amino]ethyl-8-(4-methylsulfonobenzyl)-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine.By the method of Example 4,7-[2-ethyl(2-hydroxyethyl)amino]ethyl-8-(4-methylsulfonobenzyl)-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthineis reduced with hydrazine hydrate or hydrogen gas in the presence of apalladium catalyst to yield3-[2-(4-aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-8-(4-methylsulfonobenzyl)-1-propylxanthinefree base. The corresponding hydrochloride salt is then made on exposureto an excess of hydrogen chloride in solution.

EXAMPLE 17 Synthesis of3-[2-(4-Aminophenyl)ethyl]-7-(2-ethylamino)ethyl-8-(4-methylsulfonobenzyl)-1-propylxanthineFree Base or Hydrochloride Salts

By the method of Example 2,4-methylsulfonophenylacetic acid is reactedwith 5,6-diamino-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (6) to yield3-[2-(4-nitrophenyl)ethyl]-8-(4-methylsulfonobenzyl)-1-propylxanthine.By the method of Example 3,3-[2-(4-nitrophenyl)ethyl]-8-(4-methylsulfonobenzyl)-1-propylxanthine,is reacted with sodium carbonate, 1,2-dichloroethane and ethylamine toyield7-(2-ethylamino)ethyl-8-(4-methylsulfonobenzyl)-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine.By the method of Example4,7-(2-ethylamino)ethyl-8-(3-methylsulfonobenzyl)-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthineis reduced with hydrazine hydrate or hydrogen gas in the presence of apalladium catalyst to yield3-[2-(4-aminophenyl)ethyl]-7-(2-ethylamino)ethyl-8-(4-methylsulfonobenzyl)-1-propylxanthinefree base. The corresponding hydrochloride salt is then made on exposureto an excess of hydrogen chloride in solution.

EXAMPLE 18 Synthesis of3-[2-(4-Aminophenyl)ethyl]-7-(2,2-diethylamino)ethyl-8-(4-methylsulfonobenzyl)-1-propylxanthineFree Base or Hydrochloride Salts

By the method of Example 2,4-methylsulfonophenylacetic acid is reactedwith 5,6-diamino-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (6) to yield3-[2-(4-nitrophenyl)ethyl]-1-8-(4-methylsulfonobenzyl)-1-propylxanthine.By the method of Example 3, is reacted with sodium carbonate,1,2-dichloroethane and diethylamine to yield7-(2,2-diethylamino)ethyl-8-(4-methylsulfonobenzyl)-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine.By the method of Example4,7-(2,2-diethylamino)ethyl-8-(4-methylsulfonobenzyl)-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthineis reduced with hydrazine hydrate or hydrogen gas in the presence of apalladium catalyst to yield3-[2-(4-aminophenyl)ethyl]-7-(2,2-diethylamino)ethyl-8-(4-methylsulfonobenzyl)-1-propylxanthinefree base. The corresponding hydrochloride salt is then made on exposureto an excess of hydrogen chloride in solution.

EXAMPLE 19 Synthesis of3-[2-(4-Aminophenyl)ethyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-(3-methoxypropyl)xanthine

By methods well known in the art 3-methoxypropyl isocyanate is convertedinto 8-benzyl-3-[2-(4-nitrophenyl)ethyl]-1-(3-methoxypropyl)xanthine. Bythe method of Example 3, this substance is alkylated with a mixture of1,2-dichloroethane, sodium carbonate and 2-(ethylamino)ethanol to yield8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-[2-(4-nitrophenyl)ethyl]-1-(3-methoxypropyl)xanthine.By the method of Example 4 this substance is reduced with hydrazinehydrate or hydrogen gas in the presence of a palladium catalyst to yield3-[2-(4-aminophenyl)ethyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-(3-methoxypropyl)xanthinefree base. The corresponding hydrochloride salt is then made on exposureto an excess of hydrogen chloride in solution.

EXAMPLE 20 Synthesis of3-[2-(4-Aminophenyl)ethyl]-8-benzyl-7-(2-ethylamino)ethyl-1-(3-methoxypropyl)xanthine

By methods well known in the art 3-methoxypropyl isocyanate is convertedinto 8-benzyl-3-[2-(4-nitrophenyl)ethyl]-1-(3-methoxypropyl)xanthine. Bythe method of Example 3, this substance is alkylated with a mixture of1,2-dichloroethane, sodium carbonate and ethylamine to yield8-benzyl-7-(2-ethylamino)ethyl-3-[2-(4-nitrophenyl)ethyl]-1-(3-methoxypropyl)xanthine.By the method of Example 4 this substance is reduced with hydrazinehydrate or hydrogen gas in the presence of a palladium catalyst to yield3-[2-(4-aminophenyl)ethyl]-8-benzyl-7-(2-ethylamino)ethyl-1-(3-methoxypropyl)xanthinefree base. The corresponding hydrochloride salt is then made on exposureto an excess of hydrogen chloride in solution.

EXAMPLE 21 Synthesis of3-[2-(4-Aminophenyl)ethyl]-8-benzyl-7-(2,2-diethylamino)ethyl-1-(3-methoxypropyl)xanthine

By methods well known in the art 3-methoxypropyl isocyanate is convertedinto 8-benzyl-3-[2-(4-nitrophenyl)ethyl]-1-(3-methoxypropyl)xanthine. Bythe method of Example 3, this substance is alkylated with a mixture of1,2-dichloroethane, sodium carbonate and diethylamine to yield8-benzyl-7-(2,2-diethylamino)ethyl-3-[2-(4-nitrophenyl)ethyl]-1-(3-methoxypropyl)xanthine.By the method of Example 4 this substance is reduced with hydrazinehydrate or hydrogen gas in the presence of a palladium catalyst to yield3-[2-(4-aminophenyl)ethyl]-8-benzyl-7-(2,2-diethylamino)ethyl-1-(3-methoxypropyl)xanthinefree base. The corresponding hydrochloride salt is then made on exposureto an excess of hydrogen chloride in solution.

EXAMPLE 22 Synthesis of3-[2-(4-Aminophenyl)ethyl]-8-benzyl-1-(3-dimethylaminopropyl)-7-[2-ethyl(2-hydroxyethyl)amino]ethylxanthine

By methods well known in the art 3-dimethylaminopropyl isocyanate isconverted into8-benzyl-3-[2-(4-nitrophenyl)ethyl]-1-(3-dimethylaminopropyl)xanthine.By the method of Example 3, this substance is alkylated with a mixtureof 1,2-dichloroethane, sodium carbonate and 2-(ethylamino)ethanol toyield8-benzyl-1-(3-dimethylaminopropyl)-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-[2-(4-nitrophenyl)ethyl]xanthine.By the method of Example 4 this substance is reduced with hydrazinehydrate or hydrogen gas in the presence of a palladium catalyst to yield3-[2-(4-aminophenyl)ethyl]-8-benzyl-1-(3-dimethylaminopropyl)-7-[2-ethyl(2-hydroxyethyl)amino]ethylxanthinefree base. The corresponding hydrochloride salt is then made on exposureto an excess of hydrogen chloride in solution.

EXAMPLE 23 Synthesis of3-[2-(4-Aminophenyl)ethyl]-8-benzyl-1-(3-dimethylaminopropyl)-7-(2-ethylamino)ethylxanthine

By methods well known in the art 3-dimethylaminopropyl isocyanate isconverted into8-benzyl-3-[2-(4-nitrophenyl)ethyl]-1-(3-dimethylaminopropyl)xanthine.By the method of Example 3, this substance is alkylated with a mixtureof 1,2-dichloroethane, sodium carbonate and ethylamine to yield8-benzyl-1-(3-dimethylaminopropyl)-7-(2-ethylamino)ethyl-3-[2-(4-nitrophenyl)ethyl]xanthine.By the method of Example 4 this substance is reduced with hydrazinehydrate or hydrogen gas in the presence of a palladium catalyst to yield3-[2-(4-aminophenyl)ethyl]-8-benzyl-1-(3-dimethylaminopropyl)-7-(2-ethylamino)ethylxanthinefree base. The corresponding hydrochloride salt is then made on exposureto an excess of hydrogen chloride in solution.

EXAMPLE 24 Synthesis of3-[2-(4-Aminophenyl)ethyl]-8-benzyl-7-(2,2-diethylamino)ethyl-1-(3-dimethylaminopropyl)xanthine

By methods well known in the art 3-dimethylaminopropyl isocyanate isconverted into8-benzyl-3-[2-(4-nitrophenyl)ethyl]-1-(3-dimethylaminopropyl)xanthine.By the method of Example 3, this substance is alkylated with a mixtureof 1,2-dichloroethane, sodium carbonate and diethylamine to yield8-benzyl-1-(3-dimethylaminopropyl)-7-(2,2-diethylamino)ethyl-3-[2-(4-nitrophenyl)ethyl]xanthine.By the method of Example 4 this substance is reduced with hydrazinehydrate or hydrogen gas in the presence of a palladium catalyst to yield3-[2-(4-aminophenyl)ethyl]-8-benzyl-7-(2,2-diethylamino)ethyl-1-(3-dimethylaminopropyl)xanthinefree base. The corresponding hydrochloride salt is then made on exposureto an excess of hydrogen chloride in solution.

EXAMPLE 25 Synthesis of3-[2-[4-(6-Aminohexanoyl)aminophenyl]ethyl]-8-benzyl-7-(2,2-diethylamino)ethyl-1-propylxanthine

By methods well known in the art,3-[2-(4-aminophenyl)ethyl]-8-benzyl-7-(2,2-diethylamino)ethyl-1-propylxanthineis reacted with 6-aminohexanoic acid and a coupling agent such as1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) toyield3-[2-[4-(6-aminohexanoyl)aminophenyl]ethyl]-8-benzyl-7-(2,2-diethylamino)ethyl-1-propylxanthine.

EXAMPLE 26 Synthesis of the Cy3B-Coupled Amido Derivative of3-[2-[4-(6-Aminohexyl-3-amidocarboxypropanoyl)]aminophenyl]ethyl]-8-benzyl-7-(2,2-diethylamino]ethyl-1-propylxanthine

By methods well known in the art,3-[2-[4-(6-aminohexyl-3-amidocarboxypropanoyl)]aminophenyl]ethyl]-8-benzyl-7-(2,2-diethylamino]ethyl-1-propylxanthineis reacted with the commercially available6,7,9,10-tetrahydro-2-carboxymethyl-14-sulfonato-16,16,18,18-tetramethyl-7aH,8aH-bisindolinium[3,2-a,3′2′-a]pyrano[3,2-c;5,6-c′]dipyridin-5-ium,N-hydroxysuccinimidyl ester (sold as Cy3B by Amersham Biosciences UKLimited, Little Chalfont, Buckinghamshire, England) and a base such asdiisopropylethylamine to yield the Cy3B-coupled amido derivative of3-[2-[4-(6-aminohexyl-3-amidocarboxypropanoyl)]aminophenyl]ethyl]-8-benzyl-7-(2,2-diethylamino]ethyl-1-propylxanthine.

EXAMPLE 27 Synthesis of3-[2-[4-(6-Aminohexyl-3-amidocarboxypropanoyl)]aminophenyl]ethyl]-8-benzyl-7-(2,2-diethylamino]ethyl-1-propylxanthine

By methods well known in the art,3-[2-(4-aminophenyl)ethyl]-8-benzyl-7-(2,2-diethylamino)ethyl-1-propylxanthineis reacted with succinyl anhydride and a base such as triethylamine toyield3-[2-[4-(3-carboxypropanoyl)aminophenyl]ethyl]-8-benzyl-7-(2,2-diethylamino)ethyl-1-propylxanthine.In turn, this substance is then reacted with 1,6-diaminohexane and acoupling agent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDC) to yield3-[2-[4-(6-aminohexyl-3-amidocarboxypropanoyl)]aminophenyl]ethyl]-8-benzyl-7-(2,2-diethylamino]ethyl-1-propylxanthine.

EXAMPLE 28 Synthesis of the Cy3B-Coupled Amido Derivative of3-[2-[4-(6-Aminohexanoyl)aminophenyl]ethyl]-8-benzyl-7-(2,2-diethylamino)ethyl-1-propylxanthine

This compound can be prepared in an analogous manner as that describedin Example 26 using corresponding starting materials.

EXAMPLE 29 Synthesis of the d-Biotin-Coupled Amido Derivative of3-[2-[4-(6-Aminohexyl-3-amidocarboxypropanoyl)]aminophenyl]ethyl]-8-benzyl-7-(2,2-diethylamino]ethyl-1-propylxanthine

By methods well known in the art,3-[2-[4-(6-aminohexyl-3-amidocarboxypropanoyl)]aminophenyl]ethyl]-8-benzyl-7-(2,2-diethylamino]ethyl-1-propylxanthineis reacted with d-biotin and a coupling agent such as1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) toyield the d-biotin-coupled amido derivative of3-[2-[4-(6-aminohexyl-3-amidocarboxypropanoyl)]aminophenyl]ethyl]-8-benzyl-7-(2,2-diethylamino]ethyl-1-propylxanthine.

EXAMPLE 30 Synthesis of Tritium Labelled3-[2-(4-Aminophenyl)ethyl]-8-benzyl-7-[1³H,2³H-[2-ethyl(2-hydroxyethyl)amino]ethyl]-1-propylxanthineFree Base and3-[2-(3-Aminophenyl)ethyl]-8-benzyl-7-[1³H,2³H-[2-ethyl(2-hydroxyethyl)amino]ethyl]-1-propylxanthineDihydrochloride Salt

By the method of Example3,8-benzyl-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine is alkylated witha mixture of tritium-labeled1,2-dichloroethane[³H-1,2-dichloroethane]and 2-(ethylamino)ethanol toyield tritium-labeled8-benzyl-7-[1³H,2³H-[2-ethyl(2-hydroxyethyl)amino]ethyl]-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine.By the method of Example 4 this substance is reduced with hydrazinehydrate or hydrogen gas in the presence of a palladium catalyst to yieldtritium-labeled 3-[2-(4-aminophenyl)ethyl]-8-benzyl-7-[1³H,2³H-[2-ethyl(2-hydroxyethyl)amino]ethyl]-1-propylxanthine free base.The corresponding tritium-labeled dihydrochloride salt is then made onexposure to an excess of hydrogen chloride in solution.

EXAMPLE 31 Synthesis of Tritium Labelled3-[2-(4-Aminophenyl)ethyl]-8-benzyl-7-[1³H,2³H-(2-ethylamino)ethyl]-1-propylxanthineFree Base or Hydrochloride Salts

By the method of Example3,8-benzyl-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine, is reacted withsodium carbonate, tritium-labeled1,2-dichloroethane[³H-1,2-dichloroethane]and ethylamine to yield8-benzyl-7-[1³H,2³H-(2-ethylamino)ethyl]-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine.By the method of Example4,8-benzyl-7-[1³H,2³H-(2-ethylamino)ethyl]-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthineis reduced with hydrazine hydrate or hydrogen gas in the presence of apalladium catalyst to yield3-[2-(4-aminophenyl)ethyl]-8-benzyl-7-[1³H,2³H-(2-ethylamino)ethyl]-1-propylxanthinefree base. The corresponding dihydrochloride salt is then made onexposure to an excess of hydrogen chloride in solution.

EXAMPLE 32 Synthesis of3-[4-(4-Aminophenyl)butyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propylxanthine

By the method of Example 2, phenylacetic acid is reacted with5,6-diamino-1-[4-(4-nitrophenyl)butyl]-3-propyluracil to yield8-benzyl-1-propyl-3-[4-(4-nitrophenyl)butyl]xanthine. In turn,5,6-diamino-3-propyl-1-[4-(4-nitroyphenyl)butyl]-3-uracil is made by thesynthetic methods of Example 1, starting with n-propyl isocyanate and4-(4-nitrophenyl)butylamine. By the methods of Example 3 and Example4,8-benzyl-3-[4-(4-nitrophenyl)butyl]-1-propylxanthine is alkylated witha mixture of 1,2-dichloroethane and 2-(ethylamino)ethanol, to afford8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-[4-(4-nitrophenyl)butyl]-1-propylxanthine,which, in turn, is reduced with hydrazine hydrate or hydrogen gas in thepresence of a palladium catalyst to yield3-[4-(4-aminophenyl)butyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propylxanthinefree base. The corresponding dihydrochloride salt is then made onexposure to an excess of hydrogen chloride in solution.

EXAMPLE 33 Synthesis of3-[4-(4-Aminophenyl)butyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propyl-8-(4-sulfonoxybenzyl)xanthine

By the method of Example 2,4-sulfonoxyphenylacetic acid is reacted with5,6-diamino-1-[4-(4-nitrophenyl)butyl]-3-propyluracil (6) to yield3-[4-(4-nitrophenyl)butyl]-1-propyl-8-(4-sulfonoxybenzyl)xanthine. Inturn, 5,6-diamino-1-[4-(4-nitrophenyl)butyl]-3-propyluracil is made bythe synthetic methods of Example 1, starting with n-propyl isocyanateand 4-(4-nitrophenyl)butylamine. By the method of Example 3,3-[4-(4-nitrophenyl)butyl]-1-propyl-8-(4-sulfonoxybenzyl)xanthine, isreacted with excess sodium carbonate, 1,2-dichloroethane and2-(ethylamino)ethanol to yield, after aqueous work-up,7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-[4-(4-nitrophenyl)butyl]-1-propyl-8-(4-sulfonoxybenzyl)xanthine.By the method of Example 4,7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-[4-(4-nitrophenyl)ethyl]-1-propyl-8-(4-sulfonoxybenzyl)xanthineis reduced with hydrazine hydrate or hydrogen gas in the presence of apalladium catalyst to yield3-[4-(4-aminophenyl)butyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propyl-8-(4-sulfonoxybenzyl)xanthine.

EXAMPLE 34 Synthesis of3-[4-(4-Aminophenyl)butyl]-7-(2-ethylamino)ethyl-1-propyl-8-(4-sulfonoxybenzyl)xanthine

By the method of Example 2,4-sulfonoxyphenylacetic acid is reacted with5,6-diamino-1-[4-(4-nitrophenyl)butyl]-3-propyluracil (6) to yield3-[4-(4-nitrophenyl)butyl]-1-propyl-8-(4-sulfonoxybenzyl)xanthine. Inturn, 5,6-diamino-1-[4-(4-nitrophenyl)butyl]-3-propyluracil is made bythe synthetic methods of Example 1, starting with n-propyl isocyanateand 4-(4-nitrophenyl)butylamine. By the method of Example 3,3-[4-(4-nitrophenyl)butyl]-1-propyl-8-(4-sulfonoxybenzyl)xanthine, isreacted with excess sodium carbonate, 1,2-dichloroethane and ethylamineto yield, after aqueous work-up,7-(2-ethylamino)ethyl-3-[4-(4-nitrophenyl)butyl]-1-propyl-8-(4-sulfonoxybenzyl)xanthine.By the method of Example 4,7-(2-ethylamino)ethyl-3-[4-(4-nitrophenyl)butyl]-1-propyl-8-(4-sulfonoxybenzyl)xanthineis reduced with hydrazine hydrate or hydrogen gas in the presence of apalladium catalyst to yield3-[4-(4-aminophenyl)butyl]-7-(2-ethylamino)ethyl-1-propyl-8-(4-sulfonoxybenzyl)xanthine.

EXAMPLE 35 Synthesis of3-[4-(4-Aminophenyl)butyl]-7-(2,2-diethylamino)ethyl-1-propyl-8-(4-sulfonoxybenzyl)xanthine

By the method of Example 2,4-sulfonoxyphenylacetic acid is reacted with5,6-diamino-1-[4-(4-nitrophenyl)butyl]-3-propyluracil (6) to yield3-[4-(4-nitrophenyl)butyl]-1-propyl-8-(4-sulfonoxybenzyl)xanthine. Inturn, 5,6-diamino-1-[4-(4-nitrophenyl)butyl]-3-propyluracil is made bythe synthetic methods of Example 1, starting with n-propyl isocyanateand 4-(4-nitrophenyl)butylamine. By the method of Example 3,3-[4-(4-nitrophenyl)butyl]-1-propyl-8-(4-sulfonoxybenzyl)xanthine, isreacted with excess sodium carbonate, 1,2-dichloroethane anddiethylamine to yield, after aqueous work-up,7-(2,2-diethylamino)ethyl-3-[2-(4-nitrophenyl)butyl]-1-propyl-8-(4-sulfonoxybenzyl)xanthine.By the method of Example 4,7-(2,2-diethylamino)ethyl-3-[4-(4-nitrophenyl)butyl]-1-propyl-8-(4-sulfonoxybenzyl)xanthineis reduced with hydrazine hydrate or hydrogen gas in the presence of apalladium catalyst to yield3-[4-(4-aminophenyl)butyl]-7-(2,2-diethylamino)ethyl-1-propyl-8-(4-sulfonoxybenzyl)xanthine.

EXAMPLE 36 Synthesis of3-[4-(4-Aminophenyl)butyl]-7-(2,2-dimethylamino)ethyl-1-propyl-8-(4-sulfonoxybenzyl)xanthine

By the method of Example 2,4-sulfonoxyphenylacetic acid is reacted with5,6-diamino-1-[4-(4-nitrophenyl)butyl]-3-propyluracil (6) to yield3-[4-(4-nitrophenyl)butyl]-1-propyl-8-(4-sulfonoxybenzyl)xanthine. Inturn, 5,6-diamino-1-[4-(4-nitrophenyl)butyl]-3-propyluracil is made bythe synthetic methods of Example 1, starting with n-propyl isocyanateand 4-(4-nitrophenyl)butylamine. By the method of Example 3,3-[4-(4-nitrophenyl)butyl]-1-propyl-8-(4-sulfonoxybenzyl)xanthine, isreacted with excess sodium carbonate, 1,2-dichloroethane anddimethylamine to yield, after aqueous work-up,7-(2,2-dimethylamino)ethyl-3-[2-(4-nitrophenyl)butyl]-1-propyl-8-(4-sulfonoxybenzyl)xanthine.By the method of Example 4,7-(2,2-dimethylamino)ethyl-3-[4-(4-nitrophenyl)butyl]-1-propyl-8-(4-sulfonoxybenzyl)xanthineis reduced with hydrazine hydrate or hydrogen gas in the presence of apalladium catalyst to yield3-[4-(4-aminophenyl)butyl]-7-(2,2-dimethylamino)ethyl-1-propyl-8-(4-sulfonoxybenzyl)xanthine.

EXAMPLE 37

(A) Tablet Amount per Tablet Active Ingredient: Compound of Formula (I)150 mg  Starch 50 mg  Microcrystalline cellulose 45 mg Polyvinylpryrrolidone (as 10% solution in water) 5 mg Sodiumcarboxymethyl starch 5 mg Magnesium stearate 1 mg Talc 1 mg

The active ingredient, starch and cellulose are passed through a No. 45mesh U.S. sieve and mixed thoroughly. The aqueous solution containingpolyvinylpyrrolidone is mixed with the resultant powder, and the mixturethen is passed through a No. 14 mesh U.S. sieve. The granules soproduced are dried at 50° C. and passed through a No. 18 mesh U.S.sieve. The sodium carboxymethyl starch, magnesium stearate and talc,previously passed through a No. 60 mesh U.S. sieve, are then added tothe granules which, after mixing, are compressed in a tablet machine toyield tablets.

(B) Capsule Amount per Capsule Active Ingredient: Compound of Formula(I) 150 mg  Starch 24 mg Microcrystalline cellulose 24 mg Magnesiumstearate  2 mgThe active ingredient, cellulose, starch and magnesium stearate areblended, passed through a No. 45 mesh U.S. Sieve, and filed into hardgelatin capsules.

(C) Intravenous Fluid Amount per bag Active Ingredient: Compound ofFormula (I) 100 mg Sterile Isotonic saline for injection 250 mlIn a sterile environment, the active ingredient is dissolved in theisotonic saline and the resulting solution is passed through a 2 micronfilter then filed into sterile intravenous fluid bags that areimmediately sealed.

In the specification above, there have been disclosed embodiments of theinvention and, although specific terms are employed, they are used in ageneric and descriptive sense only and not for purposes of limitation ofthe scope of the invention being set forth in the following claims.

1. A compound selected from the group consisting of:3-[2-(4-aminophenyl)ethyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-(3-methoxypropyl)xanthine,and3-[2-(4aminophenyl)ethyl]-8-benzyl-1-(3-dimethylaminopropyl)-7-[2-ethyl(2-hydroxyethyl)amino]ethylxanthine;and salts thereof.
 2. A compound selected from the group consisting of:3-[2-[4-(5-aminopentanoyl)aminophenyl]ethyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propylxanthine,3-[4-(4-aminophenyl)butyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-pentylxanthine,3-[4-(3-aminophenyl)butyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propylxanthine,3-[4-(3-aminophenyl)butyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-(3-fluoro)propylxanthine,3-[4-(3-aminophenyl)butyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-(3,3,3-trifluoro)propylxanthine,3-[4-(3-aminophenyl)butyl]-8-benzyl-7-2-ethyl(2-hydroxyethyl)amino]ethyl-1-(1,1,2,2,3,3,3-heptafluoro)propylxanthine,8-(3-aminobenzyl)-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-pentyl-3-(2-phenylethyl)xanthine,8-(3-aminobenzyl)-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-(2-phenylethyl)-1-propylxanthine,8-(2-aminobenzyl)-3-[2-(2-aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propylxanthine,8-(2-aminobenzyl)-3-[2-(3-aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethl)amino]ethyl-1-propylxanthine,8-(2-aminobenzyl)-3-[2-(3-aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-(3-fluoro)propylxanthine,3-[2-[2-(6-aminohexanoyl)aminophenyl]ethyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-(3-methoxypropyl)xanthine,3[2-(2-aminophenyl)ethyl]-8-benzyl-7[2-ethyl(2-hydroxyethyl)amino]ethyl-1-pentylxanthine,3[2-(4-aminophenyl)ethyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)-amino]ethyl-1-pentylxanthine,3[2-(4-aminophenyl)ethyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-(3-fluoro)propylxanthine,3[2-(2-aminophenyl)ethyl]-8-benzyl-1-(3-dimethylaminopropyl)-7-[2-ethyl(2-hydroxyethyl)amino]ethylxanthine,3-[2-(2-aminophenyl)ethyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-(3-methoxypropyl)xanthine,3-[2-(3-aminophenyl)ethyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-(3-methoxypropyl)xanthine,3-[2-(3-aminophenyl)ethyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-(3-methylsulfonylpropyl)xanthine,3-[6-(4-aminophenyl)hexyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)-amino]ethyl-1-pentylxanthine,3-[6-(2-aminophenyl)hexyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)-amino]ethyl-1-propylxanthine,3-[6-(3-aminophenyl)hexyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)-amino]ethyl-1-propylxanthine,3[6-(3-aminophenyl)hexyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)-amino]ethyl-1-(3-fluoro)propylxanthine,8-benzyl-3-[2-(3-chlorophenyl)ethyl]-7[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propylxanthine,8-benzyl-3-[2-(2,4-difluorophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-pentylxanthine,8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-[2-(3-nitrophenyl)ethyl]-1-propylxanthine,8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-[2-(isothiazol-3-yl)ethyl]-1-propylxanthine,8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-[2-(thiazol-3-yl)ethyl]-1-propylxanthine,8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-[2-(isoxazol-3-yl)ethyl]-1-propylxanthine,8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-[2-(1,3,4-oxadiazol-5-yl)ethyl]-1-pentylxanthine,8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-[2-(1,2,4-oxadiazol-5-yl)ethyl]-1-propylxanthine,8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-[2-(4-fluorophenyl)ethyl]-1-pentylxanthine,8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine,8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-[2-phenylethyl]-1-pentylxanthine,8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-[2-phenylethyl]-1-propylxanthine,3[2-(4-aminophenyl)ethyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-(3-methoxyethyl)xanthine,and3[2-(4-aminophenyl)ethyl]-8-benzyl-1-(3-dimethylaminoethyl)-7[2-ethyl(2-hydroxyethyl)amino]ethylxanthine;and salts thereof.